Evaluation of Hsp90 and mTOR inhibitors as potential drugs for the treatment of TSC1/TSC2 deficient cancer

Abstract

Inactivating mutations in either TSC1 or TSC2 cause Tuberous Sclerosis Complex, an autosomal dominant disorder, characterized by multi-system tumor and hamartoma development. Mutation and loss of function of TSC1 and/or TSC2 also occur in a variety of sporadic cancers, and rapamycin and related drugs show highly variable treatment benefit in patients with such cancers. The TSC1 and TSC2 proteins function in a complex that inhibits mTORC1, a key regulator of cell growth, which acts to enhance anabolic biosynthetic pathways. In this study, we identified and validated five cancer cell lines with TSC1 or TSC2 mutations and performed a kinase inhibitor drug screen with 197 compounds. The five cell lines were sensitive to several mTOR inhibitors, and cell cycle kinase and HSP90 kinase inhibitors. The IC50 for Torin1 and INK128, both mTOR kinase inhibitors, was significantly increased in three TSC2 null cell lines in which TSC2 expression was restored. Rapamycin was significantly more effective than either INK128 or ganetespib (an HSP90 inhibitor) in reducing the growth of TSC2 null SNU-398 cells in a xenograft model. Combination ganetespib-rapamycin showed no significant enhancement of growth suppression over rapamycin. Hence, although HSP90 inhibitors show strong inhibition of TSC1/TSC2 null cell line growth in vitro, ganetespib showed little benefit at standard dosage in vivo. In contrast, rapamycin which showed very modest growth inhibition in vitro was the best agent for in vivo treatment, but did not cause tumor regression, only growth delay.

Genomic features of Chinese small cell lung cancer

“…The prevalence of EGFR, BRCA2, TSC1, KMT2D and ALK gene alterations was higher in the Chinese cohort than in the Western population. Among those differences, BRCA2 was the well-known biomarkers for PARP inhibitors [ 23 ], and TSC1 naturally suppressed the overactivity of downstream mammalian target of rapamycin (mTOR), which indicated the potential clinical benefits of patients with TSC1 loss of function mutations from mTOR inhibitors [ 24 , 25 ]. EGFR mutation and ALK rearrangement are meaningful targetable driver alterations in lung adenocarcinoma (LUAD) and non-small-cell lung cancer (NSCLC), respectively [ 26 , 27 ].…”

The Role of Hsp90-R2TP in Macromolecular Complex Assembly and Stabilization

“…In bladder cancer cells, TSC1 facilitated Hsp90 acetylation at K407/K419, which increased its binding affinity for Hsp90 inhibitor ganetespib [ 163 ]. In contrast to bladder cancer cells, however, CAL-72 and PEER cells, which have a complete loss of TSC1 and reduced TSC2 expression, were also sensitized to ganetespib with IC 50 values of 22 and 3 nM, respectively [ 164 ]. In addition, hepatocellular cancer cell lines SNU-398, SNU-878, and SNU-886, which have a complete loss of TSC2 and normal TSC1 expression, had IC 50 values of 9, 14, and 35 nM, respectively [ 164 ].…”

“…In contrast to bladder cancer cells, however, CAL-72 and PEER cells, which have a complete loss of TSC1 and reduced TSC2 expression, were also sensitized to ganetespib with IC 50 values of 22 and 3 nM, respectively [ 164 ]. In addition, hepatocellular cancer cell lines SNU-398, SNU-878, and SNU-886, which have a complete loss of TSC2 and normal TSC1 expression, had IC 50 values of 9, 14, and 35 nM, respectively [ 164 ]. Nevertheless, these findings show that TSC1 and TSC2 influence Hsp90 activity.…”

Emerging Link between Tsc1 and FNIP Co-Chaperones of Hsp90 and Cancer

“…Accordingly, one study has evaluated mTOR and Hsp90 inhibitors in combination in TSC1 or TSC2 deficient cancer models. Unfortunately, the results were inconsistent between cell line and mouse xenograft models, as synergism between Hsp90 inhibitor (GB) and mTOR inhibitors (Torin2, rapamycin) in cell lines did not translate to increased efficacy over monotherapy in xenograft models [ 148 ]. Taken together, these studies demonstrate the potential therapeutic benefit of co-targeting Hsp90 and mTOR in BHD and TSC patients.…”